Theranostics for Pediatric Brain Cancer

小儿脑癌的治疗诊断学

基本信息

批准号：
10579205
负责人：
Heike Elizabeth Daldrup-Link
金额：
$ 66.12万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579205
关键词：
Adult Affect Animals Apoptosis Binding Sites Biosensor Blood - brain barrier anatomy Blood Vessels Brain Brain Neoplasms Cell Death Cells Child Childhood Childhood Malignant Brain Tumor Colchicine Data Development Diagnosis Diagnostic Disease remission Dose Dose Limiting Drug Delivery Systems Drug Monitoring Endothelial Cells Endothelium Enzymes FDA approved Fluorescein-5-isothiocyanate Fluorescence Microscopy Formulation Generations Glioblastoma Glioma Goals High Prevalence Horseradish Peroxidase Label Link Location MMP14 gene Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of brain Mean Survival Times Measures Mediating Microtubules Mitosis Modeling Mus Nature Nutritional Organ Outcome Pediatric Neoplasm Peptide Hydrolases Perivascular Neoplasm Permeability Pharmaceutical Preparations Pharmacotherapy Placebos Positioning Attribute Prodrugs Prognosis Proteins Radiation Rattus Recurrent disease Research Site Starvation System Therapeutic Therapeutic Agents Therapeutic Effect Toxic effect Treatment Efficacy Tubulin Tumor Suppression Tumor Tissue Vascular Endothelial Cell Vascularization Visceral antiangiogenesis therapy antitumor effect blood-brain barrier disruption cancer therapy cell killing clinical translation conventional therapy curative treatments cytotoxic density design improved improved outcome in vivo interest intravenous administration intravital microscopy iron oxide nanoparticle macromolecule nanocarrier nanoparticle neoplastic cell neuro-oncology novel novel drug class novel strategies novel therapeutics overexpression real time monitoring side effect success theranostics therapy resistant tumor tumor growth

项目摘要

THERANOSTICS FOR PEDIATRIC BRAIN CANCER Glioblastoma (GBM) is the most frequently diagnosed primary malignant brain tumor in children with median survival of less than one year. Disease recurrence is common and is caused by the presence of glioma-initiating cells (GICs) that are unreceptive to conventional therapies, underscoring the urgent need for new therapeutic options. We aim to develop a novel strategy to specifically disrupt the lifeline of GICs, without causing toxic effects to the normal brain. The highly vascularized nature of GBMs and the critical function of the perivascular niche for nutritional supply of GICs have spurred much interest in novel vascular-disruptive agents (VDAs). Intravenously administered VDAs easily reach GBM vessels and do not rely on the enhanced permeability and retention effect, which can limit the delivery of macromolecules to the tumor tissue. VDA-mediated blood vessel disruption causes efficient drug delivery to the GIC niche and starvation of many tumor cells. In contrast to classical anti-angiogenesis drugs, VDAs not only disrupt the tumor vasculature, but also cause significant GIC apoptosis through direct cytotoxic effects. While being highly effective for cancer treatment, initial VDA formulations also caused significant toxicity to the normal brain. This is particularly concerning for children, as the developing brain is more vulnerable to toxic side effects compared to the adult brain. To solve this problem, we developed novel VDA-loaded theranostic (combined therapeutic and diagnostic) nanoparticles, which are specifically activated in brain tumors by matrix metalloproteinases 14 (MMP-14). The normal brain does not express MMP-14 and therefore, does not activate the theranostic drug, thereby creating highly effective cancer therapy without side effects. The major goal of our project is to develop MMP-14-activatable theranostic nanoparticles (TNPs) for curative treatment of GBM, without causing toxicity to the normal brain. The approach relies on the high prevalence of MMP-14 in GBM, a proven MMP-14-activatable prodrug strategy, and a nanocarrier platform based on FDA-approved iron oxide nanoparticles. We hypothesize that our TNPs will be converted to an active therapeutic agent only within MMP-14-expressing tumors, releasing the therapeutic drug azademethylcolchicine and causing significant antitumor effects. In addition, we postulate that the iron oxide nanoparticle moiety will allow real-time monitoring of drug accumulation and localization at tumors with magnetic resonance imaging (MRI). In aim 1, we will evaluate whether TNP dose and VDA payload affect VDA mediated vascular disruption, blood brain barrier (BBB) breakdown and cancer-specific toxicity. In aim 2, we will investigate the link between VDA-mediated tumor microvessel disruption, microvascular endothelial cell death and GIC death. TNPs hold the potential to substantially improving therapeutic efficacy whilst simultaneously reducing dose-limiting toxicities. Realizing our goal will uncover new targets and mechanisms for successful GBM therapy, eliminate or substantially reduce off-target toxicities and provide children with brain cancers with a much needed new treatment option.

小儿脑癌的治疗学胶质母细胞瘤（GBM）是中位儿童中最常见的原发性恶性脑肿瘤生存不到一年。疾病复发是常见的，是由于存在神经胶质瘤引起的对常规疗法不受启发的细胞（GIC），强调了对新治疗的迫切需求选项。我们旨在制定一种新型策略来专门破坏GIC的生命线，而不会引起有毒对正常大脑的影响。 GBM的高度血管化性质和血管的关键功能 GIC营养供应的利基市场引起了人们对新型血管干扰剂（VDA）的极大兴趣。静脉内施用的VDA容易到达GBM容器，并且不依赖增强的渗透性和保留效应，可以限制大分子向肿瘤组织的递送。 VDA介导的血管破坏导致许多肿瘤细胞的GIC生态裂和饥饿。与经典的抗血管生成药物，VDA不仅破坏了肿瘤脉管系统，还会引起大量GIC 通过直接的细胞毒性作用凋亡。虽然对癌症治疗非常有效，但初始VDA 制剂还引起对正常大脑的显着毒性。这对儿童尤其令人担忧，因为与成人大脑相比，发育中的大脑更容易受到毒性副作用。要解决这个问题，我们开发了新颖的VDA负载疗法（治疗和诊断）纳米颗粒，通过基质金属蛋白酶14（MMP-14）在脑肿瘤中特别激活。正常的大脑不明确MMP-14，因此不会激活疗法药物，从而产生高效的癌症没有副作用的治疗。我们项目的主要目的是开发MMP-14-活活的Theranostic 纳米颗粒（TNP）用于治疗GBM的治疗，而不会引起正常大脑的毒性。这方法依赖于MMP-14在GBM中的高流行率，GBM是一种经过验证的MMP-14可行前药策略，并且基于FDA批准的氧化铁纳米颗粒的纳米载体平台。我们假设我们的TNP将是仅在表达MMP-14的肿瘤内转换为活性治疗剂，释放治疗药物氨基甲基甲基氨酸并引起明显的抗肿瘤作用。此外，我们假设氧化铁纳米颗粒部分将允许对具有磁性的肿瘤的药物积累和定位进行实时监测共振成像（MRI）。在AIM 1中，我们将评估TNP剂量和VDA有效载荷是否影响VDA中介血管破坏，血脑屏障（BBB）分解和癌症特异性毒性。在AIM 2中，我们将调查 VDA介导的肿瘤微血管破坏，微血管内皮细胞死亡与GIC之间的联系死亡。 TNP具有实质上提高治疗功效的潜力，同时降低了治疗功效剂量限制毒性。实现我们的目标将发现成功的GBM治疗的新目标和机制，消除或实质上降低脱靶毒性，并为儿童提供急需的脑癌新的治疗选择。